The broad objective of the current grant is to elucidate the regulatory principles that govern the biological outcome of signals that are generated in response to receptor tyrosine kinase (RTK) activation. A central route by which RTKs trigger intracellular signals involves the activation of Ras by its guanine nucleotide exchange factor Sos. Consequently, a major component of the current grant is aimed at defining the molecular and cellular basis for Sos-mediated Ras activation. This Competitive Revision Application, which we are submitting in response to Notice NOT-OD-09-058, entitled "NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications" seeks to augment these efforts through the integration of a novel chemical approach pioneered by our collaborator, Dr. Paramjit Arora from the Department of Chemistry, New York University. The overall goal is to develop highly specific small molecule modulators of Sos-mediated Ras activation. The strategy to be used builds on the expertise of Dr. Arora in generating short peptides that can stably maintain 1-helical conformation. Specifically, our experimental design is aimed at the generation of short stable artificial 1-helices that disrupt Ras-Sos interaction in vitro and compromise RTK-mediated Ras activation in vivo. Given the complementary expertise of the PI and Dr. Arora and the promising preliminary data, the likelihood that the proposed studies would be brought to completion within the indicated time frame is exceedingly high. PUBLIC HEALTH RELEVANCE: Signal transduction is a fundamental process that enables cells to acquire information from the extracellular environment and respond to this information appropriately. This application focuses on the establishment of new approaches to target specific signaling events. Experiments proposed herein should thus advance our molecular understanding of signal transduction processes and provide insights into signaling defects that underlie a host of human diseases.